| Tubulin β class V, encoded by TUBB5, is a β‑tubulin isotype within the tubulin family that polymerizes with α‑tubulin into heterodimers and incorporates into microtubules, which form a major structural element of the cytoskeleton and support intracellular transport, cell division, and neuronal morphogenesis. The protein contains the conserved GTP‑binding and exchangeable nucleotide‑binding regions characteristic of β‑tubulins and contributes to the longitudinal and lateral interfaces that stabilize protofilament assembly and microtubule lattice formation, while isotype‑specific sequence variation in surface‑exposed loops tunes interactions with microtubule‑associated proteins and motors. TUBB5 expression is enriched in neurogenic progenitors and the developing cerebral cortex, and β‑tubulin heterodimers containing TUBB5 participate in microtubule networks that are required for mitotic spindle formation, interkinetic nuclear migration, and neurite extension during corticogenesis. De novo missense mutations in TUBB5 identified in patients with microcephaly and structural brain malformations alter the chaperone‑dependent assembly of α/β‑tubulin heterodimers, reduce incorporation of mutant TUBB5 into microtubules or change microtubule dynamics, and disrupt progenitor cell‑cycle progression and neuronal migration during embryonic neurogenesis. Functional analysis of these disease‑associated alleles shows that perturbation of TUBB5 affects terminal differentiation of cortical neurons, modifies axonal outgrowth, reduces dendritic complexity, and alters dendritic spine density and morphology, consistent with a role for TUBB5‑containing microtubules in establishing neuronal connectivity and synaptic architecture. TUBB5 contributes to the balance between microtubule stability and dynamics that underlies spindle function, radial migration, and circuit formation, and pathogenic TUBB5 variants define a subset of tubulinopathies in which β‑tubulin isotype–specific defects produce microcephaly with complex cortical malformations and postnatal cognitive and motor impairment. |
